Desmosomes are intercellular adhesive junctions that play pivotal roles in maintaining tissue architecture, integrity and function. Desmogleins (Dsg) 1-4 are the transmembrane components of desmosomes and are the target molecules in several human autoimmune, infectious and heritable diseases highlighting their roles in cell-cell adhesion, skin barrier function, and hair follicle development. However, whether these desmogleins can mediate cell signaling under normal and diseased conditions is still poorly understood. In human, genetic mutations in the DSG2 gene results in inherited arrhythmogenic right ventricular dysplasia/cardiomyopathy. Studies of the Dsg2 null mice attest to the importance of Dsg2 during embryonic development and in stem cell growth and survival. Furthermore, Dsg2 is over-expressed in certain epithelial malignancies suggesting a role in cell proliferation and differentiation that favor of tumor development. We recently provide strong evidence that overexpression of Dsg2 in epidermal keratinocytes deregulates multiple signaling pathways associated with increased growth rate, anchorage-independent cell survival, and the development of skin tumors in vivo. These compelling results call for an in-depth investigation of novel roles of desmosomal cadherins in epithelial cell biology and skin tumor development. The long-term goal of our laboratory is to elucidate desmosome-mediated signaling at the molecular and cellular level; particularly, the differences between normal and pathogenic signaling during skin development. Our central hypothesis is that desmogleins can activate signaling events that are independent of desmosomal structure and adhesive function. We argue that the function of desmogleins strictly within the context of the desmosome is not sufficient to explain their diverse biologic effects. Thus the overall goal for this proposal is to elucidate the cellular and molecular mechanisms activated by Dsg2 that impact epithelial cell growth, survival and malignant transformation. This goal will be pursued in three Specific Aims designed to: 1) Assess the effects of Dsg2 on signaling and malignant transformation when expressed in different cell populations specifically progenitor and differentiating epithelial cells; 2) Assess the role of proteolytic processing of Dsg2 in epithelial cell growth and survival; and 3) Determine the role of caveolin-1 in Dsg2-mediated signaling and malignant transformation. The proposed work is innovative because it capitalizes on our recent discovered oncogenic role of Dsg2 and preliminary data showing complex proteolytic processing of Dsg2 and localization of Dsg2 with caveolin-1 to the caveolae, specialized lipid rafts that are involved in many key growth and survival signaling pathways. The results obtained here will enhance our understanding of desmosomal cadherins and the pathology of desmosome-associated diseases and will help identify new directions for therapeutic treatments of acquired and inherited diseases resulting from impaired desmosome function. PUBLIC HEALTH RELEVANCE: This application will help define the roles of desmosomal cadherins in modulating, not only epithelial cell-cell adhesion, but also cell growth and survival. In particular, we will focus on desmoglein 2, which is up regulated in several skin cancers. Determining the molecular mechanisms by which desmoglein 2 affects tumor growth and development has the potential of identifying new targets for therapeutic cancer treatments.